During the first award period the MRCE Aerosol Biology/Small Animal Models Core D (Core D) supported smallpox disease research (using ectromelia, monkeypox, and vaccinia viruses) as this disease was one of the most intensely modeled in Region 7. With licensure of Modified Vaccinia Ankara (MVA) and the availability of ACAM 2000 (derived from Dryvax), and phase I clinical trials of orthopoxvirus antivirals, ST-246 and CMX001, there is a diminishing need for in vivo testing of additional orthopoxvirus therapeutics and prophylactics. There is, however, still much to learn concerning the innate immune response to orthopxviruses and other infectious agents. The capacity of Core D to create additional models for use in basic research and prophylactic and therapeutic efficacy testing was under-scored by the development of the following five lethal challenge models: influenza virus A in C57BL/6-sfaH